Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells
Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells
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DOI：
10.1016/j.jconrel.2018.03.035
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发表时间：
2018-05-28
影响因子：
10.8
通讯作者：
Mateo, V
中科院分区：
文献类型：
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作者：
Le Moignic, A.;Malard, V;Mateo, V
直接施用编码肿瘤抗原的合成mRNA的临床试验证明了安全性和肿瘤特异性免疫应答的诱导。它们适当地递送到树突状细胞（DC）需要它们对RNA酶降解的保护和对剂量减少的更特异性。脂质-聚合物-RNA脂质复合物（Lipid-Polymer-RNA lipopolyplexes，LPR）是一种有吸引力的mRNA递送系统，其具有含甘露糖的糖脂的设备，特异性存在于DC膜上的内吞受体是一种有价值的策略。在本工作中，我们评估了用α-D-吡喃甘露糖苷的三天线功能化的LPR（triMN-LPR）的能力，涉及（i）它们与表达CD 209/DC-SIGN和CD 207/Langerin的细胞系、人和小鼠DC和其他造血细胞群体的结合，（ii）体内免疫后诱导的免疫应答的性质和（iii）它们的治疗性抗癌疫苗效率。我们证明，triMN-LPR皮内注射给C57 BL/6小鼠后两天提供了局部炎症反应的高诱导，随后在相应的引流淋巴结中募集和激活DC。这与疫苗接种部位皮肤产生CCR 7和CXCR 4驱动DC迁移有关。在E7编码的mRNA triMN-LPR疫苗接种后检测到大量E7特异性T细胞。当在三种治疗性临床前鼠肿瘤模型（例如表达E7的TC 1细胞、表达OVA的EG 7细胞和表达MART-1的B16 F0细胞）中进行评估时，携带编码相应抗原的mRNA的triMN-LPR在初始肿瘤接种后7天接种的小鼠中显著发挥治愈性应答。这些结果提供了证据，证明triMN-LPR引起有效的刺激性免疫应答，允许在小鼠中进行治疗性抗癌疫苗接种。这种mRNA制剂应考虑用于人类的抗癌疫苗接种。
Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Their proper delivery to dendritic cells (DCs) requires their protection against RNase degradation and more specificity for dose reduction. Lipid-Polymer-RNA lipopolyplexes (LPR) are attractive mRNA delivery systems and their equipment with mannose containing glycolipid, specific of endocytic receptors present on the membrane of DCs is a valuable strategy. In this present work, we evaluated the capacity of LPR functionalized with a tri-antenna of a-D-mannopyranoside (triMN-LPR) concerning (i) their binding to CD209/DC-SIGN and CD207/Langerin expressing cell lines, human and mouse DCs and other hematopoietic cell populations, (ii) the nature of induced immune response after in vivo immunization and (iii) their therapeutic anti-cancer vaccine efficiency. We demonstrated that triMN-LPR provided high induction of a local inflammatory response two days after intradermal injection to C57BL/6 mice, followed by the recruitment and activation of DCs in the corresponding draining lymph nodes. This was associated with skin production of CCR7 and CXCR4 at vaccination sites driving DC migration. High number of E7-specific T cells was detected after E7-encoded mRNA triMN-LPR vaccination. When evaluated in three therapeutic pre-clinical murine tumor models such as E7-expressing TC1 cells, OVA-expressing EG7 cells and MART-1-expressing B16F0 cells, triMN-LPR carrying mRNA encoding the respective antigens significantly exert curative responses in mice vaccinated seven days after initial tumor inoculation. These results provide evidence that triMN-LPR give rise to an efficient stimulatory immune response allowing for therapeutic anti-cancer vaccination in mice. This mRNA formulation should be considered for anti-cancer vaccination in Humans.